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PDBsum entry 4gj2
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Transferase/transferase inhibitor
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PDB id
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4gj2
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References listed in PDB file
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Key reference
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Title
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Lead optimization of a 4-Aminopyridine benzamide scaffold to identify potent, Selective, And orally bioavailable tyk2 inhibitors.
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Authors
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J.Liang,
A.Van abbema,
M.Balazs,
K.Barrett,
L.Berezhkovsky,
W.Blair,
C.Chang,
D.Delarosa,
J.Devoss,
J.Driscoll,
C.Eigenbrot,
N.Ghilardi,
P.Gibbons,
J.Halladay,
A.Johnson,
P.B.Kohli,
Y.Lai,
Y.Liu,
J.Lyssikatos,
P.Mantik,
K.Menghrajani,
J.Murray,
I.Peng,
A.Sambrone,
S.Shia,
Y.Shin,
J.Smith,
S.Sohn,
V.Tsui,
M.Ultsch,
L.C.Wu,
Y.Xiao,
W.Yang,
J.Young,
B.Zhang,
B.Y.Zhu,
S.Magnuson.
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Ref.
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J Med Chem, 2013,
56,
4521-4536.
[DOI no: ]
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PubMed id
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Abstract
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Herein we report our lead optimization effort to identify potent, selective, and
orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used
structure-based design to discover 2,6-dichloro-4-cyanophenyl and
(1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved
TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization
eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12
(IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity
and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model,
compound 37 showed statistically significant knockdown of cytokine interferon-γ
(IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be
sufficient to block the IL-12 pathway in vivo.
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